Mitsui Tetsuya, Nemoto Takayuki, Miyake Taiji, Nagao Shunsuke, Ogawa Kotaro, Kato Motohiro, Ishigai Masaki, Yamada Hideyuki
Preclinical Research Department, Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan (Te.M., T.N.,Ta.M., S.N., K.O., M.K., M.I.); and Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (H.Y.)
Preclinical Research Department, Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan (Te.M., T.N.,Ta.M., S.N., K.O., M.K., M.I.); and Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (H.Y.).
Drug Metab Dispos. 2014 Sep;42(9):1540-7. doi: 10.1124/dmd.114.057935. Epub 2014 Jul 8.
The accurate prediction for the body clearance of a novel drug candidate by humans during the preclinical stage contributes to its successful development. To improve the predictability of human hepatic clearance, we focused on CYP3A4, which is involved in the metabolism of more than 50% of all currently marketed drugs. In this study, we investigated the validity of the in vivo model using transgenic mice carrying the human CYP3A4 gene and lacking their own Cyp3a genes (CYP3A4-Tg mice). The CYP3A4 activity toward its substrates in liver microsomes was similar in CYP3A4-Tg mice and humans. As for the clearance, six CYP3A4 substrates (alprazolam, felodipine, midazolam, nifedipine, nitrendipine, and quinidine) were given intravenously to CYP3A4-Tg mice, and their hepatic intrinsic clearance (CLint,h) was evaluated. A regression analysis of the data obtained indicated that the CLint,h values of six substrates in CYP3A4-Tg mice were highly correlated with those in humans (R(2) = 0.95). This correlation could be improved by correcting the CLint,h values by the relative contribution of artificially expressed CYP3A4 to the overall metabolism in the mice. From these findings, it is reasonable to expect that the CLint,h of a particular drug in humans is predictable by applying the CLint,h obtained in CYP3A4-Tg mice to a regression line prepared in advance. The variance of the CLint,h prediction by this method was evaluated and found to be within a range of 2-fold of the regression value. These results suggest that the CYP3A4-Tg mouse model has the potential to accurately predict the human hepatic clearance of CYP3A4 substrates.
在临床前阶段准确预测新型候选药物在人体中的体内清除率有助于其成功研发。为提高对人体肝脏清除率的预测能力，我们聚焦于CYP3A4，目前超过50%的市售药物的代谢都与之相关。在本研究中，我们研究了使用携带人类CYP3A4基因且自身缺乏Cyp3a基因的转基因小鼠（CYP3A4-Tg小鼠）建立的体内模型的有效性。CYP3A4-Tg小鼠肝脏微粒体中其对底物的活性与人类相似。关于清除率，将六种CYP3A4底物（阿普唑仑、非洛地平、咪达唑仑、硝苯地平、尼群地平和奎尼丁）静脉注射给CYP3A4-Tg小鼠，并评估其肝脏内在清除率（CLint,h）。对所得数据进行回归分析表明，CYP3A4-Tg小鼠中六种底物的CLint,h值与人类的CLint,h值高度相关（R(2) = 0.95）。通过用人为表达的CYP3A4对小鼠整体代谢的相对贡献校正CLint,h值，这种相关性可以得到改善。基于这些发现，通过将在CYP3A4-Tg小鼠中获得的CLint,h应用于预先制备的回归线来预测人体中特定药物的CLint,h是合理的。评估了用该方法预测CLint,h的方差，发现其在回归线值的2倍范围内。这些结果表明，CYP3A4-Tg小鼠模型具有准确预测CYP3A4底物人体肝脏清除率的潜力。
